title: PPARα-mediated responses in human adult liver stem cells: In vivo/in vitro and cross-species comparisons.
abstract: The peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that regulates a variety of biological processes including lipid metabolism and energy homeostasis. Peroxisome proliferators (PPs) are carcinogens in rodents, while humans are resistant to peroxisome proliferation and carcinogenesis. In this study, we examined the differential gene expression elicited by clofibrate (CLO) and WY-14,643 (WY) in C57BL/6 mouse liver compared to responses in human HepG2 hepatoma and HL1-1 adult stem cells. Mice were gavaged with sesame oil, 300mg/kg CLO or WY for 2, 4, 8, 12, 18 or 24h, or daily for 4 or 14 days. Although no significant changes in body weight gain were observed, WY induced relative liver weight at 4 and 14 days. Genome-wide hepatic gene expression analysis identified 719 and 1443 differentially expressed unique genes elicited by CLO and WY, respectively (|fold change|>1.5, P1(t)>0.99). Functional analysis associated the gene expression changes with lipid metabolism, transport, cell cycle and immune response. Most differentially expressed genes were in common to both treatments and clustered together only at early time points (2-8h). Complementary QRT-PCR studies in human HL1-1 and HepG2 cells treated with 50μM WY or DMSO for 1, 2, 4, 8, 12, 24 or 48h identified a minimal number of conserved orthologous responses (e.g., Pdk4, Adfp and Angptl4) while some genes (i.e., Bmf, a tumor suppressor) exhibited induction in human cells but repression in mice. These data suggest that PPs elicit species-specific PPARα-mediated gene expression.
authors.affiliation: Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, MI 48824, United States; Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, United States. Electronic address: kimsun5@msu.edu.
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: N
authors.initials: N
authors.lastname: Kiyosawa
authors.forename: L D
authors.initials: LD
authors.lastname: Burgoon
authors.forename: C C
authors.initials: CC
authors.lastname: Chang
authors.forename: T R
authors.initials: TR
authors.lastname: Zacharewski
mesh_terms: D000818:Animals; D002994:Clofibrate / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D047493:PPAR alpha / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*
chemical_list: D047493:PPAR alpha; D011743:Pyrimidines; C006253:pirinixic acid; D002994:Clofibrate; D004121:Dimethyl Sulfoxide
keywords: Clofibrate; Comparative; Human liver stem cell; Liver; PPAR alpha; Toxicogenomics; WY-14,643